Critical events in prostate tumorigenesis likely include the abnormal activation and expression of specific genes. Using RNA expression profiling techniques, we have identified a gene, AIPC (Activated In Prostate Cancer), that is up-regulated at the RNA and protein levels in human prostate tumors and tumor-derived cell lines. Evaluation of AIPC protein expression using tissue microarrays demonstrated significant and abundant AIPC expression in malignant and PIN lesions, but not benign glands. Moreover, AIPC expression is highly androgen-dependent in normal prostate epithelium and is down-regulated in responsive, but not in non-responsive, human prostate tumors treated with neoadjuvant hormonal therapy. Continued high levels of AIPC expression in hormonally non-responsive human prostate tumors suggest that AIPC transcription may 'escape' hormonal regulation during tumor progression. Furthermore, sequence analysis revealed that the AIPC protein encodes six PDZ domains, protein-protein binding domains that likely recruit, bind and coordinate the activities of other proteins. One AIPC protein ligand is beta-catenin, a molecule involved in cell-cell adhesion, cellular proliferation and malignant transformation. Beta-catenin may act as an initial downstream effector of AIPC by activating the TCF/LEF-mediated transcription of several genes implicated in cellular proliferation and/or malignant transformation. The protein products of some of these genes are transcription factors themselves and may recognize consensus binding sites in the AIPC promoter, thus contributing to constitutive and high levels of AIPC expression even under conditions of hormone ablation. Based on these studies, we hypothesize that AIPC transcriptional regulation may 'escape' hormonal regulation during prostate tumor progression, and that the AIPC protein itself may contribute to the development of the hormone insensitive phenotype in human prostate tumors. To test this hypothesis, we have proposed three Specific Aims: SPECIFIC AIM 1: Define the mechanism of AIPC transcriptional up-regulation in malignant cells. SPECIFIC AIM 2: Characterize AIPC/catenin interactions and examine the potential contribution of these interactions to malignant transformation in the prostate. SPECIFIC AIM 3: Elucidate the mechanism responsible for continued AIPC protein expression under conditions of androgen deprivation in human prostate cancers.